Azasugars compounds, synthesis method and applications thereof

A technology for compounds and carbohydrates, applied in the fields of active ingredients of heterocyclic compounds, organic chemistry, drug combination, etc., can solve the problems of low overall yield, cumbersome preparation process, unclear structure-activity relationship research, etc., to achieve strong cellular immunity and Humoral immune activity, the effect of novel structure

Active Publication Date: 2010-06-23
PEKING UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the existing azasaccharide compounds, especially the alkylated azasaccharide compounds, still have the disadvantages of cumbersome preparation process, low overall yield, and unclear structure-activity relationship research.

Method used

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  • Azasugars compounds, synthesis method and applications thereof
  • Azasugars compounds, synthesis method and applications thereof
  • Azasugars compounds, synthesis method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Synthesis of Example 1 Compound 3a ((3S, 4R, 5S)-3,4,5-three (benzyloxy)-1-n-decylpiperidin-2-one)

[0045] Compound 1 ((2S, 3R, 4S, 5S)-3,4,5-tris(benzyloxy)-tetrahydro-2-methoxy-6-vinyl-dihydropyran) (200 mg, 0.45mmol) was dissolved in anhydrous methanol, cooled to -78°C, and slowly passed into O 3 Gas until the reaction solution turns blue. After stirring at -78°C for 3 minutes, N was slowly introduced into the 2 Until the blue color disappears, add n-decylamine (178 μl, 0.90 mmol), NaCNBH 3 (59mg, 0.9mmol) and ZnCl 2 (12mg, 0.09mmol), reflux reaction 2h, add saturated NaHCO under ice-cooling 3 Quenches the reaction. Methanol was distilled off under reduced pressure, the residue was dissolved in ethyl acetate (80m), washed twice with saturated NaCl solution, anhydrous NaCl 2 SO 4 After drying, filter. The filtrate was concentrated under reduced pressure to remove ethyl acetate, and the residue was separated and purified by normal pressure column chromatograph...

Embodiment 2

[0048] Synthesis of Example 2 Compound 3b ((3S, 4R, 5S)-3,4,5-three (benzyloxy)-1-n-nonylpiperidin-2-one)

[0049] It is prepared from compound 1 and n-nonylamine, and the specific operation steps are the same as the synthesis of compound 3a. Atmospheric column separation [eluent (V / V) petroleum ether: ethyl acetate = 8:1]. Product properties: white solid, yield 90%. 1 H NMR (300MHz, CDCl 3 )δ0.88(t, 3H, J=6.9Hz), 1.24(s, 12H), 1.49(s, 2H), 3.22-3.44(m, 4H), 3.72(dd, 1H, J=6.3, 11.1Hz ), 3.82(t, 1H, J=6.9Hz), 3.98(d, 1H, J=6.9Hz), 4.55-4.19(m, 5H), 5.12(d, 1H, J=11.1Hz), 7.26-7.44 (m, 15H); 13 C NMR (75MHz, CDCl 3 )δ14.1, 22.6, 26.8, 27.3, 29.2, 29.3, 29.4, 31.8, 47.0, 47.8, 72.1, 73.7, 74.1, 76.2, 79.4, 82.1, 127.6, 127.7, 127.8, 127.9, 128.2, 128.3, 128.7, 1 , 137.9, 138.0, 168.4; HRMS: Calcd for C 27 h 28 o 6 [M+Na] + , 566.3241; Found, 566.3240.

Embodiment 3

[0050] Synthesis of Example 3 Compound 3c ((3S, 4R, 5S)-3,4,5-three (benzyloxy)-1-n-octylpiperidin-2-one)

[0051] Prepared from compound 1 and n-octylamine, the specific operation steps are the same as the synthesis of compound 3a. Atmospheric column separation [eluent (V / V) petroleum ether: ethyl acetate = 8:1]. Product properties: white solid, yield 82%. 1 H NMR (300MHz, CDCl 3 )δ0.87(t, 3H, J=6.3Hz), 1.25(s, 10H), 1.49(s, 2H), 3.22-3.44(m, 4H), 3.72(dd, 1H, J=6.6, 11.4Hz ), 3.83(t, 1H, J=7.2Hz), 3.98(d, 1H, J=6.9Hz), 4.54-4.79(m, 5H), 5.12(d, 1H, J=11.4Hz), 7.25-7.44 (m, 15H); 13 C NMR (75MHz, CDCl 3 )δ14.4, 23.0, 27.1, 27.7, 29.5, 29.7, 32.1, 47.4, 48.1, 72.4, 74.0, 74.5, 76.6, 79.7, 82.4, 128.0, 128.1, 128.2128.3, 128.6, 128.7, 128.8, 138.31, 138.1 , 138.4, 168.8.Anal.Calcd for C 34 h 43 NO 4 : C, 77.09; H, 8.18; N, 2.64; Found: C, 76.86; H, 7.92; N, 2.65; + .

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Abstract

The invention discloses azasugars compounds, a synthesis method and applications thereof, which belongs to the field of medicinal chemistry. Glucose, galactose, mannose, acetylglucosamine and ribose are used as raw materials, and an N-alkylating azasugars compound is synthesized by a one-pot continuous synthesis process. In the structure, carbonyl is used to replace hydroxymethyl, the structure is novel, the activity is good in the applications of treating Gauher diseases and being used as immune inhibitors, and the toxicity of most of compounds is low as proved by the cytotoxic test. As proved by the skin fibroblast test of mutant Gaucher disease patients, the azasugars compounds have the pharmacological activity in treating Gaucher disease. As proved by the MTT test and skin transplanting mouse, the azasugars compounds have strong cell immune and humoral immune activity.

Description

technical field [0001] The present invention relates to azasaccharide compounds, in particular to a class of N-alkylated azasaccharide compounds, pharmaceutically acceptable salts thereof and synthesis methods thereof. The present invention also relates to the N-alkylated azasaccharide compounds The medicinal use in the treatment of Gaucher's disease and as an immunosuppressant belongs to the field of medicinal chemistry. Background technique [0002] Gaucher's disease (also known as Gaucher's disease or Gaucher's disease in Chinese, Gaucher's disease is also called cerebrosidosis) is a kind of lysosomal storage disease, which is a congenital lipid metabolism disorder. Chromosomal recessive genetic disease (T.D. Butters, Curr. Opin. Chem. Biol 2007, 11, 412.). Due to the lack of β-glucocerebrosidase (β-Glc), its substrate glucocerebroside cannot be degraded normally, but is stored in lysosomes, and lysosomes swell accordingly, and cell functions are seriously affected. Inv...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/36C07D211/72A61K31/44A61P37/06
CPCY02P20/55
Inventor 叶新山王冠男
Owner PEKING UNIV
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